Disease relevance of T11TS-induced T-cell signal transduction through the CD2-mediated calcineurin-NFAT pathway: Perspectives in glioma immunotherapy

摘要

Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell - antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma-induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated "alternative pathway" of calcineurin-NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this "alternative pathway" of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-theta (PKC-theta), calcineurin and nuclear factor for activation of T-cells (NEAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door - one which is directed towards clinical studies for glioma-immunotherapy using T11TS. (C) 2015 Elsevier Ltd. All rights reserved.